Circulating tumor cells are cells recovered from a simple blood draw that reflect the molecular pathology of cancer, may constitute the seeds for metastases, and represent an analyte to longitudinally measure and direct clinical decisions in cancer patients. The LiquidBiopsy platform and protocols support high throughput recovery and the specificity to support direct targeted resequencing. The platform will be evaluated with metastatic breast cancer patients by determining whether the legacy marker Epcam or an expanded cocktail recover more mutation bearing CTC. The patient cohort will then be extended to analyze CTC mutation profiles using a 50 oncogene hotspot panel at baseline and progression. These profiles will be compared to germline and tissue biopsy sequence to evaluate the molecular relationship between CTC and tissue biopsy and the predictive capability of CTC derived mutational information. The validated process and instrumentation can recover mutational information from blood samples of metastatic breast cancer patients. By examining a cohort of 60 patients with metastatic disease, the study is powered to determine whether CTC mutations are predictive of disease progression. The LiquidBiopsy platform represents an innovative methodology that supports clinical access to genetic information from CTC supporting this first example of a CTC-based diagnostic tool.